The hypocholesterolemic action of TA-7552 and its effects on cholesterol metabolism in the rat

The hypocholesterolemic property of 1-(3,4-dimethoxyphenyl)-2,3- bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene (TA-7552) and its effects on Cholesterol metabolism were investigated in the rat. TA-7552 incorporated into a hypercholesterolemic diet at a concentration of 0.2% and administered for 7 days reduced serum Cholesterol by 72% and liver Cholesterol by 90%, and its minimal effective dose was 0.01% in the diet. Its hypocholesterolemic effect was associated with an elevation of serum HDL-cholesterol. Inclusion of 0.1% TA-7552 in the normal laboratory chow accelerated fecal excretion of 14C derived from orally administered 4-[14C]Cholesterol or carbonyl-[14C]taurocholate. The net amounts of fecal neutral sterols and bile acids were markedly increased by the same treatment. Hepatic bile acid production and hepatic and intestinal Cholesterol biosynthesis as measured by Cholesterol 7 alpha-hydroxylase activity and 1-[14C]acetate incorporation into tissue Cholesterol, respectively, were both stimulated by the drug treatment. All these data indicate that this hypocholesterolemic agent inhibits intestinal absorption of both Cholesterol and bile acids and compensatorily stimulates hepatic production of bile acids and Cholesterol.